A number of treatments involving the administration of single drugs are currently recommended for relief of pain including neurological pain. The single administration of narcotic analgesics, gamma (γ)-aminobutyric acid (GABA) analogs such as gabapentin, pregabalin and baclofen, antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to display pain alleviating properties in the clinic and in various animal models.
Despite the benefits derived from the current single drug pain relief regimens, these regimens have disadvantages. One area of concern relates to the incidence of unwanted side effects caused by many of the pain treatment regimens available today. Narcotic analgesics, such as morphine, are sparingly prescribed for chronic pain because of the well-known addictive effects and central nervous system (CNS) side effects and gastrointestinal side effects resulting from their single administration.
Another concern of the current pain treatment regimens relates to their effectiveness. Many single active ingredients such as antidepressant agents or GABA analogs employed in current pain relief regimens cannot achieve adequate pain alleviation even at their maximum approved therapeutic doses in certain severe pain states. In addition to not achieving adequate pain alleviation, increasing the drug dose may produce an increase in unwanted side effects such as cognitive impairment, nausea, and constipation.
Furthermore, other concerns of GABA analogs and many narcotic analgesics relate to their less favorable pharmacokinetic and physiological properties. Many orally administrated opioid molecules are extensively metabolized by digestive organs before reaching systemic circulation. Rapid systemic clearance and saturable absorption of some of the GABA analogs have limited these drugs to reach their full potential in treatment of pain and other CNS disorders. These sub-optimal properties often lead to less than adequate efficacy and unwanted side effects in patients.
Sustained released formulations are a conventional method to address the issue of rapid systemic clearance, as it is well known to those skilled in the art (e.g., “Remingtion's Pharmaceutical Sciences,” Philadelphia College of Pharmacy and Science, 17th Edition, 1985). GABA analogs, such as baclofen, gabapentin and pregabalin are not absorbed through the large intestine. Rather, these compounds are typically absorbed in the small intestine by the neutral amino transporter systems (Jezyk et al., Pharm. Res., 1999, 16, 519-526). The rapid passage of conventional tract has prevented the successful application of sustained release approach to these GABA analogs.
In view of these concerns, it is evident that there is a need for an improved pain regimen that provides an improved therapeutic benefit (i.e., reduced severity and/or frequency of pain) and/or reduces the incidence of unwanted side effects caused by many of the current regimens. In addition, improving pharmacokinetic profile of GABA analogs will also lead to more customized dosing regimens according to patients' need.